Skeletal metastases associated with advanced prostate cancer (PCa) continue to kill more than 29,000 men per year in the United States. Metastatic disease remains incurable because a population of cancer cells within a tumor are resistant to all known natural and synthetic compounds. Resistance to a therapy may be solely cell intrinsic, therefore present in a treatment-nave setting, as well as be induced through external selective pressure via therapeutic treatment. How and when drug resistance arises has profound implications to understand tumorigenesis as well as to guide treatment and management of disease. Our preliminary data and other recent studies have demonstrated that the appearance of a subset of morphologically distinct cancer cells, polyploid giant cancer cells (PGCCs), is associated with therapeutic intervention, including taxane-based chemotherapy in castrate resistant prostate cancer (CRPCa). Consistent with other studies, we further show that PGCCs are often multinucleated, have elevated genomic content, can be found in biopsies of metastatic tumor tissue, and are reported to possess senescent as well as stem-like properties. PGCCs also have a highly motile mesenchymal phenotype and are enriched in metastases, suggesting that, in addition to their role in therapeutic resistance, they may be important initiators of metastatic spread. While multiple mechanisms of drug and stress resistance have been described, the totality of our preliminary data leads us to hypothesize that PGCCs survive the intrinsic (microenvironment and metastasis) and extrinsic (therapeutic) stresses associated with cancer progression in a novel manner by existing in a reversible G0 state. In Specific Aim 1 we will determine how and when PGCCs are formed. Further, we will measure PGCCs in mouse and human PCa tissues across clinical disease states. In Specific Aim 2 we will demonstrate that reversible senescence underlies a common mechanism of stress resistance in PGCCs. We will also assess if PGCCs exhibit cancer stem cell properties that permit them to reinitate proliferation. In Specific Aim 3 we will demonstrate that PGCCs are important initiators of metastasis. In addition, we will measure circulating PGCCs in murine models and patients in different clinical disease states. The results of our studies will fundamentally change our understanding of how tumors develop resistance to stress as well as evolve the ability to metastasize.